There is an increasing recognition that, in the long term, total joint replacement (TJR) may be associated with adverse local and remote tissue responses that are mediated by the degradation products of prosthetic materials. There has been particular interest in the metallic degradation products of TJR because of the known toxicities of the metallic elements that comprise the implant alloys. In this long term study, we have been investigating metal release, transport, storage and excretion in patients with total hip (THR) and knee (TKR) replacements. In our first grant period, we have demonstrated that i) patients with loose titanium base alloy THR demonstrate significant elevations in serum titanium concentration that correlate with articular wear; ii) in some cases, these elevated concentrations can be one to two orders of magnitude higher than control values; iii) in patients with TKRs, delaminated patellar components and carbon fiber reinforced polyethylene articular surfaces are associated with dramatic elevations of serum titanium; iv) serum cobalt levels are elevated and correlated to the degree of corrosion in failed modular femoral THR components; v) patients with well-functioning THR and TKR demonstrated elevated serum titanium when followed in a prospective longitudinal manner; and vi) in patients with well-functioning implants, there is local elevation in tissue metal content as will as deposition of metal within the spleen, liver and regional lymph nodes. These findings taken together suggest that the magnitude of metal release transport and storage associated with TJR components is greater than what was anticipated. We propose to expand on these studies to (l) quantify metal release in the prospective study group which will be three to eight years post-operative - an interval in which complications related to the implant are more prevalent; (2) characterize the association of local and systemic metal concentration and tissue reaction with corrosion in modular THR components; (3) prospectively follow patients after revision surgery who have demonstrated significant elevations in serum metal content to determine if serum metal transport diminishes with time; and (4) expand our autopsy retrieval program to characterize not only tissue metal levels and systemic distribution of particulate wear debris but also the tissue and cellular localization of these degradation products. These studies are deemed critical in order to understand the prospective risks to patients undergoing total joint arthroplasty.